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Serine hydrolases play important roles in signaling and human metabolism, yet little is known about their functions in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human protease dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Functional studies reveal that BT4193 is a true homolog of hDPP4 that can be inhibited by FDA-approved type 2 diabetes medications targeting hDPP4, while the other is a misannotated proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and that loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. However, neither function is dependent on BT4193 proteolytic activity, suggesting a scaffolding or signaling function for this bacterial protease.

Background aims: Extracellular vesicles (EVs) harvested from conditioned media of human mesenchymal stromal cells (MSCs) suppress acute inflammation in various disease models and promote regeneration of damaged tissues. After successful treatment of a patient with acute steroid-refractory graft-versus-host disease (GVHD) using EVs prepared from conditioned media of human bone marrow–derived MSCs, this study focused on improving the MSC-EV production for clinical application. Methods: Independent MSC-EV preparations all produced according to a standardized procedure revealed broad immunomodulatory differences. Only a proportion of the MSC-EV products applied effectively modulated immune responses in a multi-donor mixed lymphocyte reaction (mdMLR) assay. To explore the relevance of such differences in vivo, at first a mouse GVHD model was optimized. Results: The functional testing of selected MSC-EV preparations demonstrated that MSC-EV preparations revealing immunomodulatory capabilities in the mdMLR assay also effectively suppress GVHD symptoms in this model. In contrast, MSC-EV preparations, lacking such in vitro activities, also failed to modulate GVHD symptoms in vivo. Searching for differences of the active and inactive MSC-EV preparations, no concrete proteins or miRNAs were identified that could serve as surrogate markers. Conclusions: Standardized MSC-EV production strategies may not be sufficient to warrant manufacturing of MSC-EV products with reproducible qualities. Consequently, given this functional heterogeneity, every individual MSC-EV preparation considered for the clinical application should be evaluated for its therapeutic potency before administration to patients. Here, upon comparing immunomodulating capabilities of independent MSC-EV preparations in vivo and in vitro, we found that the mdMLR assay was qualified for such analyses.

International audience; Estimating tropical forests vertical structure using remote sensing is a challenge. Active sensors such as lowfrequency Synthetic Aperture Radar (SAR) operating at P-band, with a wavelength of ∼ 69 cm wavelength, and Light Detection and Ranging (LiDAR) are able to penetrate thick vegetation layers. While NASA’s Global Ecosystem Dynamics Investigation (GEDI) is collecting spaceborne liDAR data, the ESA’s next Earth Explorer BIOMASS mission will acquire multiple acquisitions over the same areas to form three-dimensional images through SAR tomography (TomoSAR) technique. Our study shows the potential value of GEDI and TomoSAR acquisitions in producing accurate estimates of forests vertical structure. By analyzing airborne P-band TomoSAR, airborne LiDAR, and spaceborne GEDI LiDAR at a tropical forest site in Paracou, French Guiana, South America, we show that both GEDI and P-band TomoSAR can directly measure surface, vegetation heights, and vertical profiles with high resolution and precision. Airborne TomoSAR is of higher quality than GEDI due to better penetration properties and precision. However, the GEDI vegetation height root-meansquare error is less than 5 m, for an average forest height value around 30 m at the Paracou site, which is similar to the expected performance of the future spaceborne BIOMASS mission. These results suggest GEDI measurements, i.e. shots with sensitivity greater than 98%, will provide a good reference of forest structure to calibrate the BIOMASS mission algorithms.

Background Timely diagnosis and use of contact precautions for Clostridioides difficile infection (CDI) is key to prevent spread in hospital settings. Empowering nursing staff to order stool tests and proactively implement precautions has been shown to reduce hospital acquired CDI. Our institution established a nurse driven CDI order set in 2019, however only 1% of tests were ordered by nurses in the past year. The goal of this quality improvement project was to understand current use of the nurse-driven CDI order set using a novel humble inquiry approach. Methods We used humble inquiry, an interview approach that poses questions while building relationships with participants through humility, curiosity, and active listening skills to explore barriers to utilization of a nurse driven CDI order set. Two nursing students at a 182-bed Veterans Health Administration (VA) hospital were trained to use humble inquiry and a three-item interview guide. A convenience sample of nurses and nursing assistants were interviewed about a) what they know about the nurse driven CDI order set, b) where there is documentation about the order set and c) barriers to use of the order set (if any). Interviews were conducted from January to April 2022. Demographics were analyzed descriptively. Interview data and the experience of conducting humble inquiry were analyzed using manifest content analysis. Results Interviews (n=19) with nurses (n=16) and nursing assistants (n=3) revealed the majority (13/19 = 68%) were not aware of the nurse driven CDI order set. Of those aware, most were able to identify the location of information on their unit and where to document in the electronic medical record. The two most common barriers included lack of awareness of the order set and patient reluctance to disclose their bowel habits. Delay in providers reading notes (3/19=16%) and lack of PPE during COVID (1/19= 5%) were also identified as barriers. The nursing students reported the humble inquiry approach allowed participants to be the “experts” and “teachers”. Table IIllustrative quotes from interview answers and associated demographic information. Conclusion The humble inquiry method was valuable in understanding viewpoints and identifying barriers to utilization of a nurse drive CDI order set. Lack of awareness of the order set and patient modesty were identified as barriers and may be targeted for future interventions. Disclosures All Authors: No reported disclosures.

1. 使用基于振动的损伤检测方法进行结构健康监测. 2. 基于材料力学性能评价提出一种新的结构健康监测方法. 1. 通过一个被称为损失函数 (LF) 的新指标描述材料粘弹性参数与振动参数之间的相关性. 2. 使用卷积神经网络 (CNN) 提取自动特征和损坏敏感性, 以评估结构状况. 1. 测量真实桥梁的振动响应. 2. 在频域中进行信号处理以揭示振动能量损失. 3. 基于深度学习和 CNN 对桥梁状况进行分类. 1. 在真实结构中总是会发生能量扩散. 2. 基于振动能量损失变化的 LF 评估, 可以对桥梁进行健康监测. 3. 基于深度学习的能量扩散评估是可实现的, 并且在多个实际桥梁中具有较高的可实施性.

Singular spectrum analysis (SSA) has been employed effectively for analyzing in the time-frequency domain of time series. It can collaborate with data-driven models (DDMs) such as Artificial Neural Networks (ANN) to set up a powerful tool for mechanical fault diagnosis (MFD). However, to take advantage of SSA more effectively for MFD, quantifying the optimal component threshold in SSA should be addressed. Also, to exploit the managed mechanical system adaptively, the variation tendency of its physical parameters needs to be caught online. Here, we present a bearing fault diagnosis method (BFDM) based on ANN and SSA that targets these aspects. First, a multi-feature is built from pure mechanical properties distilled from the vibration signal of the system. Relied on SSA, the measured acceleration signal is analyzed to cancel the high-frequency noise. The remaining components take part in building a multi-feature to establish a database for training the ANN. Optimizing the number of the kept components is then carried out to obtain a dataset called Tr_Da. Based on Tr_Da, we receive the optimal ANN (OANN). In the next period, at each checking time, another database called Test_Da is set up online following the same way of building the Tr_Da. The compared result between the encoded output and the output of the OANN corresponding to the input to be Test_Da provides the bearing(s) health information. An experimental apparatus is built to evaluate the BFDM. The obtained results reflect the positive effects of the method.

Serine hydrolases play important roles in signaling and human metabolism, yet little is known about the functions of these enzymes in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human protease dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Functional studies reveal that BT4193 is a true homolog of hDPP4 while the other is misannotated and is a proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and is inhibited by FDA-approved type 2 diabetes drugs that target hDPP4. Loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. Taken together, our findings suggest that serine hydrolases contribute to gut microbiota dynamics and may be off-targets for existing drugs that could cause unintended impact on the microbiota.

Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M (Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.

A wide range of microbial pathogens is capable of entering the gastrointestinal tract, causing infectious diarrhea and colitis. A finely tuned balance between different cytokines is necessary to eradicate the microbial threat and to avoid infection complications. The current study identified IL-33 as a critical regulator of the immune response to the enteric pathogen Citrobacter rodentium. We observed that deficiency of the IL-33 signaling pathway attenuates bacterial-induced colitis. Conversely, boosting this pathway strongly aggravates the inflammatory response and makes the mice prone to systemic infection. Mechanistically, IL-33 mediates its detrimental effect by enhancing gut permeability and by limiting the induction of protective T helper 17 cells at the site of infection, thus impairing host defense mechanisms against the enteric pathogen. Importantly, IL-33-treated infected mice supplemented with IL-17A are able to resist the otherwise strong systemic spreading of the pathogen. These findings reveal a novel IL-33/IL-17A crosstalk that controls the pathogenesis of Citrobacter rodentium-driven infectious colitis. Manipulating the dynamics of cytokines may offer new therapeutic strategies to treat specific intestinal infections.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of signaling lipids with anti-inflammatory and anti-diabetic properties. However, the endogenous regulation of FAHFAs remains a pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS–based lipidomics analyses, and activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolases, control FAHFA levels in vivo in both genetic and pharmacologic mouse models. Tissues from mice lacking ADTRP (Adtrp-KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs particularly isomers with the ester bond at the 9(th) carbon due to decreased FAHFA hydrolysis activity. The levels of other lipid classes were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs. Complementing these genetic studies, we also identified a dual AIG1/ADTRP inhibitor, ABD-110207, which is active in vivo. Acute treatment of WT mice with ABD-110207 resulted in elevated FAHFA levels, further supporting the notion that AIG1 and ADTRP activity control endogenous FAHFA levels. However, loss of AIG1/ADTRP did not mimic the changes associated with pharmacologically administered FAHFAs on extent of upregulation of FAHFA levels, glucose tolerance, or insulin sensitivity in mice, indicating that therapeutic strategies should weigh more on FAHFA administration. Together, these findings identify AIG1 and ADTRP as the first endogenous FAHFA hydrolases identified and provide critical genetic and chemical tools for further characterization of these enzymes and endogenous FAHFAs to unravel their physiological functions and roles in health and disease.

Modern Synthetic Aperture Radar (SAR) missions provide an unprecedented massive interferometric SAR (InSAR) time series. The processing of the Big InSAR Data is challenging for long-term monitoring. Indeed, as most deformation phenomena develop slowly, a strategy of a processing scheme can be worked on reduced volume data sets. This paper introduces a novel ComSAR algorithm based on a compression technique for reducing computational efforts while maintaining the performance robustly. The algorithm divides the massive data into many mini-stacks and then compresses them. The compressed estimator is close to the theoretical Cramer–Rao lower bound under a realistic C-band Sentinel-1 decorrelation scenario. Both persistent and distributed scatterers (PSDS) are exploited in the ComSAR algorithm. The ComSAR performance is validated via simulation and application to Sentinel-1 data to map land subsidence of the salt mine Vauvert area, France. The proposed ComSAR yields consistently better performance when compared with the state-of-the-art PSDS technique. We make our PSDS and ComSAR algorithms as an open-source TomoSAR package. To make it more practical, we exploit other open-source projects so that people can apply our PSDS and ComSAR methods for an end-to-end processing chain. To our knowledge, TomoSAR is the first public domain tool available to jointly handle PS and DS targets.

Estimating consistent large-scale tropical forest height using remote sensing is essential for understanding forest-related carbon cycles. The Global Ecosystem Dynamics Investigation (GEDI) light detection and ranging (LiDAR) instrument employed on the International Space Station has collected unique vegetation structure data since April 2019. Our study shows the potential value of using remote-sensing (RS) data (i.e., optical Sentinel-2, radar Sentinel-1, and radar PALSAR-2) to extrapolate GEDI footprint-level forest canopy height model (CHM) measurements. We show that selected RS features can estimate vegetation heights with high precision by analyzing RS data, spaceborne GEDI LiDAR, and airborne LiDAR at four tropical forest sites in South America and Africa. We found that the GEDI relative height (RH) metric is the best at 98% (RH98), filtered by full-power shots with a sensitivity greater than 98%. We found that the optical Sentinel-2 indices are dominant with respect to radar from 77 possible features. We proposed the nine essential optical Sentinel-2 and the radar cross-polarization HV PALSAR-2 features in CHM estimation. Using only ten optimal indices for the regression problems can avoid unimportant features and reduce the computational effort. The predicted CHM was compared to the available airborne LiDAR data, resulting in an error of around 5 m. Finally, we tested cross-validation error values between South America and Africa, including around 40% from validation data in training to obtain a similar performance. We recommend that GEDI data be extracted from all continents to maintain consistent performance on a global scale. Combining GEDI and RS data is a promising method to advance our capability in mapping CHM values.

Summary A reciprocal interaction exists between the gut microbiota and the immune system. Regulatory T (Treg) cells are important for controlling immune responses and for maintaining the intestinal homeostasis but their precise influence on the gut microbiota is unclear. We studied the effects of Treg cell depletion on inflammation of the intestinal mucosa and analysed the gut microbiota before and after depletion of Treg cells using the DEpletion of REGulatory T cells (DEREG) mouse model. DNA was extracted from stool samples of DEREG mice and wild‐type littermates at different time‐points before and after diphtheria toxin application to deplete Treg cells in DEREG mice. The V3/V4 region of the 16S rRNA gene was used for studying the gut microbiota with Illumina MiSeq paired ends sequencing. Multidimensional scaling separated the majority of gut microbiota samples from late time‐points after Treg cell depletion in DEREG mice from samples of early time‐points before Treg cell depletion in these mice and from gut microbiota samples of wild‐type mice. Treg cell depletion in DEREG mice was accompanied by an increase in the relative abundance of the phylum Firmicutes and by intestinal inflammation in DEREG mice 20 days after Treg cell depletion, indicating that Treg cells influence the gut microbiota composition. In addition, the variables cage, breeding and experiment number were associated with differences in the gut microbiota composition and these variables should be respected in murine studies., In this study we showed that temporal regulatory T (Treg) cell depletion in DEpletion of REGulatory T cells mice was accompanied by an increase of the relative abundance of the phylum Firmicutes of the gut microbiota, indicating that Treg cells affect the gut microbiota composition. In addition, Treg cell depletion was associated with intestinal inflammation. Furthermore, the variables cage, breeding and experiment number affected the gut microbiota composition and should be respected in murine gut microbiota studies

Prior studies have found mixed results regarding whether there are cultural differences in the age-related positivity effect, defined as older adults' showing a greater bias in cognitive processing for positively over negatively and neutrally valenced information relative to younger adults. This study attempted to address this controversy by examining visual attention toward culturally relevant versus irrelevant pictures that differed in valence among younger and older U.S. Americans and Hong Kong Chinese. Preferences (attentional biases toward particular valence) and effectiveness (whether the attentional biases are associated with better mood) were also distinguished. Findings revealed that regardless of cultural relevance of the pictures, older U.S. Americans showed more gaze preference for positive over negative pictures compared to their younger counterparts; this age difference was not found among Hong Kong Chinese. In contrast, older Hong Kong Chinese showed better mood as a function of more gaze preference for positive over negative pictures. Younger Hong Kong Chinese and younger and older U.S. Americans did not show this association. The results suggest that an age-related positivity effect exists at the preference level for U.S. Americans but at the effectiveness level for Chinese. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Our studies demonstrated the critical role of Histone deacetylases (HDACs) in the regulation of nephrogenesis. To better understand the key pathways regulated by HDAC1/2 in early nephrogenesis, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) of HDAC1/2 on isolated nephron progenitor cells (NPCs) from mouse E16.5 kidneys. Our analysis revealed that 11,802 (40.4%) of HDAC1 peaks overlap with HDAC2 peaks, further demonstrates the redundant role of HDAC1 and HDAC2 during nephrogenesis. Common HDAC1/2 peaks are densely concentrated close to the transcriptional start site (TSS). GREAT Gene Ontology analysis of overlapping HDAC1/2 peaks reveals that HDAC1/2 are associated with metanephric nephron morphogenesis, chromatin assembly or disassembly, as well as other DNA checkpoints. Pathway analysis shows that negative regulation of Wnt signaling pathway is one of HDAC1/2's most significant function in NPCs. Known motif analysis indicated that Hdac1 is enriched in motifs for Six2, Hox family, and Tcf family members, which are essential for self-renewal and differentiation of nephron progenitors. Interestingly, we found the enrichment of HDAC1/2 at the enhancer and promoter regions of actively transcribed genes, especially those concerned with NPC self-renewal. HDAC1/2 simultaneously activate or repress the expression of different genes to maintain the cellular state of nephron progenitors. We used the Integrative Genomics Viewer to visualize these target genes associated with each function and found that HDAC1/2 co-bound to the enhancers or/and promoters of genes associated with nephron morphogenesis, differentiation, and cell cycle control. Taken together, our ChIP-Seq analysis demonstrates that HDAC1/2 directly regulate the molecular cascades essential for nephrogenesis.